We propose to study the regulation of serine and glycine biosynthesis in bacterial and mammalian cells with the object of defining and understanding the mechanisms which control metabolism. The bacterial system is controlled by end product inhibition of enzyme activity. The responsible enzyme has been crystallized, and the mechanism of serine inhibition will be investigated at the chemical level in order to elucidate how small molecules influence protein structure. The basis for the constancy in enzyme levels in bacteria will be investigated by combining genetic and enzymological techniques. Mammalian cells regulate the production or stability of the enzymes responsible for serine biosynthesis. The fluctuations that occur in the levels of the enzymes responsible for serine biosynthesis in mammalian cells will be investigated to determine whether the rates of synthesis or degradation are affected. The enzymes responsible for the production and degradation of glycine also change activity with growth conditions. The compounds responsible for the alterations in these enzymatic systems will be identified and the mechanisms by which they interact with the processing of macromolecules determined. The ultimate aim of this project is to understand how cells maintain balanced growth and to explain how aberrant regulatory processes cause pathological and malignant conditions.